Human African Trypanosomiasis (HAT) is a fatal disease caused by Trypanosoma brucei spp. There is a need for new treatments for HAT because current treatments are costly, difficult to administer and frequently toxic. We have identified several oxaborole 6-carboxamides that demonstrate potent activity against T. brucei brucei in vitro and exhibit efficacy against both the acute and chronic central nervous system stages of HAT in mouse models. Exposure of T. b. brucei to oxaboroles leads to significant changes in shape, reduction in cellular size and detached flagella at the time of death. In vitro studies performed to characterize the relationship between killing of T. brucei and oxaborole exposure demonstrate an early (6-9 hrs) onset of trypanocidal activity as shown by the inability of the parasites to generate ATP. Parasite commitment to death in vitro occurs with similar kinetics even when the compound is washed out 2-3 hours following exposure. For mechanism of action studies, fluorescently tagged oxaborole analogues have been synthesized and incubated with T. brucei parasites to identify sub-cellular localization. In addition, representative compounds have been immobilized on agarose matrices for use in affinity capture of parasite target proteins which will be identified by mass spectrometry and data base searches. Collectively these studies, which use AN3520 as an example compound, will provide a better understanding of how oxaboroles exert their trypanocidal effects and enable us to develop valuable pharmacokinetic/pharmacodynamic models to ensure appropriate drug delivery for treatment of HAT.
Nare, B.; Mercer, L.; Bowling, T.; Orr, M.; Chen, D.; Sligar, J.; Jenks, M.; Noe, A.; Wring, S.; Bacchi, C.; Yarlett, N.; Freund, Y.; Plattner, J.; Jarnagin, K.; Don, R.; Jacobs, R. In Vitro Pharmacodynamics and Mechanism of Action Studies of Oxaborole 6-Carboxamides: A New Class of Compounds for the Treatment of African Trypanosomiasis. (2009)